Hormone intermediates and preparation of same



Patented July 4, 1944 UNITED STATES PATENT OFFICE HORMONE INTERMEDIATES AND PREPARATION OF SAME Russell Earl Marker, state College, Pa., mimito Parke, Davis a Company, Detroit, Mich, a corporation of Michigan No Drawing. Application June 30, 1941, Serial No. 400,559

11 Claims. (Cl. 280-3975) This invention relates to new hormone intermediates and preparation of the same. More particularly it relates to the preparation of a new i class 01' hormone intermediates which may be wr-cm-cm-cn-cmon designated as 16,20-dihydroxypregnane com- 5 D pounds.

In my copending application Serial No. 393,667, filed May 15, 1941, it is shown that steroidal sapogenins can be converted into a new class III or these formulae, n and m best explain the which I designate as formation of the exo-dihydro-pseudo-sapogenins.

sapogenins.

The pseudo-sapogenins are characterized by the fact that they contain a new type of side chain which undergoes distinctive reactions.

It is believed that the properties 01' the exodihydro-pseudo-sapogenins are best explained if the side chain attached to ring D of the cyclopentanoperhydrophenanthrene nucleus be repre- Thus' the Pseudmsamgemns are unsaturated sented by one of the following formulae:

bromine and therefore readily decolorize a solution of bromine in acetic acid. On treatment with acids, for example, with alcoholic hydrochloric acid, the pseudo-sapogenins are isomerized to the corresponding steroidal sapogenins. 20 The side chain of the pseudo-sapogenins contains a reactive hydroxyl group which may be acylated, for example, acetylated.

The pseudo-sapogenins can be hydrogenated,

for example, as set forth in my copending application Serial No. 382,450, filed March 8, 1941, to give another new class of compounds which I have designated as cxo-dihydro-pseudo-sapogenins. In contrast to the pseudo-sapogenins, the exo-dihydro-pseudo-sapogenins show no unso saturation to bromine in acetic acid, nor are they afiected by alcoholic hydrochloric acid. Like the pseudo-sapogenins, however, the exo-dihydropseudo-sapogenins contain in the side chain a reactive hydroxyl group which may be acylated, for

example, acetylated.

It is believed that the properties of the pseudosapogenins are best explained if the side chain attached to ring D of the cyclopentanoperhydrophenanthrene nucleus be represented the following partial formulae:

01 these, V seems to account best for the transformations described in the present invention.

It will be observed that the partial Formulae I, II, III, IV and V all contain a reactive hydroxyl group. This hydroxyl group may be acylated to yield compounds which may then be by one of 40 designated as exo-acylates.

In the case oi'jboth the terms exo-acylate and exo-dihydro-pseudo-sapogenin, the prefix exo" has the same significance that it does in other branches of organic chemistry, namely, that the I particular function involved is exterior to a ring system and in a position not known with greater certainty.

In the copending application of Russell Earl v Marker, Harry Means Crooks, Jr., and Eugene Leroy Wittle, Serial No. 393,666. flied May 15,

1941, there is described the oxidation of pseudosapogenin exo-acylates and oi exo-dihydropseudo-sapogenin exo-acylates to give a new class of esters. These new esters are designated 20*- keto 16 (t-acyloxyisocaprooxwpregnane compounds and they may be represented by the partial formula:

CHI

In all of the foregoing formulae (I to VII inelusive) and in other partial formulae which may follow, it will be understood that only the new 'distinctive structural features of my new compounds are indicated and that the structure in regard to rings A and B may be of any type known in steroid chemistry.

Now I have discovered that when thenew esters, that is to say the -keto-l6-(6) -acyloxyisocaprooxypregnane compounds described in the copending application Serial No. 393,666, filed May 15, 1941, are reduced there are obtained useful intermediates for the preparation of hormones.

My invention may be practiced according to any of the following ways:

The 20 keto 16 (a acyloxyisoca'prooxy pregnane compounds may be catalytically hydrogenated, as for example, by shaking the 20-keto- 16- (6-acyloxyisocapro6xy-) -pregnane compound with platinum oxide and acetic acid in a hydrogen atmosphere for about an hour at room temperature.

In an alternative mode of reduction the 20- keto-16-(6-acy1oxyisocapro6xy-) -pregnane compound may be reduced by treatment with the combination of (a) a primary or secondary alcohol, and (b) an aluminum alcoholate or a compound of the formula Z-Mg-OR, where Z is an anion such as chloride, sulfate, or p-toluenesulfonate, Mg is magnesium, and OR is an aicoholate group such as isopropylate, t-butylate, and the like.

Reduction of the 20-keto-16-(t-acyloxyiso caprooxyo-pregnane compound according to either of the methods mentioned above leads to the formation of the same type of compound, namely, the corresponding zmpihydroxy-iti-(tacyloxyisocaprolixy-) -pregnane compound which may be represented by the structural formula,

CHI

VIII

In most instances it is convenient to treat the to remove the ester group at Cit, thereby forming 2 O(t),16-dihydroxypregnane compounds representable by the following partial formula,

CHI

isocapro6xy-) -pregnane compound with the combination of an alkali metal and a alcohol or other substance containing reactive hydrogen, for example, the combination of sodium metal and ethyl alcohol, leads to the formation of a 20(a)hydroxy-pregnane compound which may be represented by the following partial formula,

According to yet another modification, my invention may be practiced as follows: The 20- keto-16- (6-acyloxyisocaprooxy-) -pregnane compound is subjected to hydrolytic treatment with an acidic or an alkaline reagent thereby forming a A"-20-keto-pregnene compound and the latter is reduced then with the combination of (a) a primary or secondary alcohol and (b) an aluminum alcoholate or a compound of the formula ZMg-OR, where Z is a anion such as chloride, sulfate, or p-toluene-sulfonate, Mg is magnesium, and OR is an alcoholate group such as isopropylate, t-butylate, and the like. Thus there is obtained a A -20-(p) -hydroxypregnene compound which may be represented by the following partial formula;

CH; I H-omp 0n catalytic hydrogenation, compounds of the type K1 are reduced to 20- (p) -hydroxypregnane compounds which may be represented by the following partial formula,

CH: off-0am I D Where the terms 20-()-hydroxy and 2045)- hydroxy occur in this specification it will be unassaees 3 derstood that these terms refer to the two acetic anhydride at 200 0., thereby forming plm r theoretically possible. See further R. E. pseudo-diosgenin diacetate. After crystalliza- Marker et al., J. Am. Chem. Soc., 59, 2291 (1937) tion from methanol, the pseudo-diosgenin diace- It will be appreciated, in view of what is distate has a melting point of 97-100" C. v closed, that my invention comprehends a new 5 (b) Pseudo-diosgenin diacetate is oxidized class of steroids useful as intermediates for the with chromic anhydride in acetic acid at 28 C., preparation of hormones. This new class of as set forth more fully inthe copending applicasteroids may be designated as 20,(p),16-dihytion of Russell Earl Marker, Harry Means droxy-pregnane compounds. As already indi- Crooks, Jr., and Eugene Le Roy Wittle, Serial No. cated, these newcompounds may have in rings 393,666, filed May 15, 1941. Thus there is ob- A and B of the steroid nucleus almost any of tained the corresponding -keto-16-(6-acyloxythe structural features known in steroid chemisocaprooxy) -pregnane compound of melting istry. Thus, rings A and B may be saturated or point 85-86 C. This compound is believed to unsaturated and may be unsubstituted or may have the structure,

bear substituents such as halogen, hydroxyl, carand it may be designated as A -pregnenediolboxyl, amino, ether or like groups or groups hy- 3(3) ,16-one-20 3-acetate-l6- (6 acetoxy isocapdrolyzable to these. roate.

My invention also comprehends derivatives of (c) To 2 g. of the product, melting point 85-86 these 20, (p), 16-dihydroxypregnane compounds, 0., designated as A -pregnenediol-3-(p),16-onesaid derivatives being hydrolyzable to yield said 20 3-acetate-16-(6-acetoxy) -isocaproate,in 200 cc. 20, (,6), lfi-dihydroxypregnane compounds. of dry isopropyl alcohol is added 15 g. of sodium These derivatives comprise, for example, esters n Small P The mixture is reflux d fo and ethers such as the acetates, benzoates, about an hour or until all the sodium has disstearates, benzyl ethers and the like, They ar solved. Thereupon water is added and the mixprepared, for example, by the action of acylating ture extracted well with ether. The ethereal or etherifying agents n th parent bin l layer is washed with water and then the ether is Generally, the ew compounds of my invention removed on a steam bath. The residue is crysare representable by the following formula, tallized from dilute ne and r m dilute CH. methanol and thus yields A pregnenediolon. on. 305*),20-(11) of melting point I'll-176 C,

34:09) The structure of the above product is shown by the fact that it may be hydrogenated in the presence of glacial acetic acid and a platinum oxide catalyst to yield al1o-pregnanediol-3- M. (mac-(a) ofmelting point 214-216" 0. J Example 2 where X and X are members of the class con- (a) A mixture of 5 g. of A -pregnenedi01-3- sisting of hydroxyl and groups hydrolyzable to (p),16-one-20 B-acetate 16(6-acetoxy)-isocaprohydroxyl; where the symbol n. represents 11 ate, 10 g. of aluminum isopropylate and 400 cc. earbon-to-carbon double bonds in the A--B porof dry isopropyl alcohol is refluxed for seven tion of the steroid nucleus, n having one of the hours. Then the mixture is distilled through a values 0, 1, 2 and 3; and where the symbol mY column over-a period of five hours and the resirepresents in substituents attached to the due is refluxed with 500 cc. of 2% methanolic methylene carbon atoms of the A-B portion of potassium hydroxide for thirty minutes. The the steroid nucleus, said substituents being semixture thus obtained is diluted with water and lected from the class consisting of the precipitate collected and crystallized from OH methanol. Thus there is obtained A -pregnenetriol-3-(p),16,20(p) of melting point 281-285 C.

When refluxed for thirty minutes with an excess of acetic anhydride it forms a triacetate and groups hydmlyzable to which may .be isolated in the usual manner. 01! After crystallization from ether-pentane it has a melting point of 143 C.

H (b) A mixture of 500 mgs. of th above A .111. having one of the values 0, 1, 2 and 3, and D 8 fl M 3 0 triacetate. 1 o m and n being so chosen that their platinum oxide catalyst and 200 cc. of glacial does not exceed the value 3, acetic acid is shaken under hydrogen at 45 lbs. My invention may be illustr t d by th 1 1- pressure for one hour. The solution is filtered lowing examples, and the filtrate concentrated in vacuo. The res- Example 1 idue is allo-pregnenetriol-3(p),16,20(,B) m

. tate. It is hydrolyzed by refluxing it for fifteen (a) Diosgenin is treated as set forth more fully minutes with an excess or a 2% alcoholic P t in my copending application, Serial No. 382,451, sium hydroxide solution. Then water is added filed March 8, 1941, for six to fifteen hours with and the precipitated material collected and re- 4' aasaeaa:

crystallized from alcohol. Thus there is obobtained, meltingpoint 266-280 0., has the emtained allo-pregnanetriol-Mp) ,16,20(p) of meltpirical iormula :18:00: and is an allo-p inspoint 285-287 C; -nanetriol-8(p), 1630().

The same allo-presnanetriol-3(s),16,20(p), When the above triol is refluxed in acetic meltins point 281-285? (2., is obtained by reduc- 5 'anhydride solution for thirty minutes and the in: allopregnanediol-3(p),16-one-20 ,3-acetat'eacetylated mixture worked up, there is obtained 16(t-acetoxy)-isocaproate (obtained, for examan allo-presnanetrioi triacetate oi melting point ple. as described in Example 30 with aluminum 161-163 C.

. isopropylate and isopropyl alcohol according to The sam 31lo-pre mnemo1m obtained by the e method set forth n th s p s anh or m analosous ca alytic .hydrosmation and subsem example, I quent hydrolysis of the A'-pregnenediol-3(p),16

Example. 3 a -m lwe om-isoc pmate oi melting point 84-86 C. (a) Dihydro-pseudo-tigogenin diacetate, meltin: point 122-120 0., is prepared, for example, p e 4 as set forth inmy copendins application, Serial (a) h -pregnenediol-itip), 16-one-20 3-ace- No. 382,450, filed March 8, 1941, by the catalytic tate-16(6-acetoxy) -isocaproate, is obtained, for hydrogenation of pseudo-diosgenin diacetate. example, as described in Example 1, parts a (b) Dihydro-pseudo-tisoflenin. diacetate is and b. oxidized with chromic anhydride in acetic acid 20 (1)) Three hundred milligrams of th above at 28 C., as set forth more fully in the copending ester is refluxed in 20 cc. of alcohol with 300 application of Russell Earl Marker, Harry Means mzs. or potassium hydroxide to: thirty minutes. Crooks, Jr., and Eugene Le Roy Wittle, Serial Then water is added and the'organic material No. 393,666, filed May 15, 1941. Thus there is removed with ether. The ethereal layer is obtained the compound of melting point 102- washed with water and then the solvent is re- 104 C. representable by the following formula, moved to leave a residue which may be crystalcm cm I; z r l /\N ocmcm 11-omo- -cm 0 cHr- -o This compound may be designated as allolized from acetone and i'romethyi acetate. The pregnanediol-3ip) -16-one-20 S-acetate 16- (8- product thus obtainedis A '"-pregna,dieno]-3- acetoxy) -isocaproate. (p) -one-20 oimelting point 213-215 Cl It does (c) The substance of melting point 102-104" 0. not depress in melting point when mixed with an designated as allo-pregnanediol-Mfi) -16-0ne-20 authentic sample. 3-acetate-16 (t-acetoxy) -isocapro ate is hydro The same a -pregnadienol-ll-(p) -one-20 may genated by shaking 2 g. or it with 3 g. of platinum be obtained when the oxidation product above oxide catalyst in 100 cc. of glacial acetic acid in is refluxed with 10% alcoholic hydrochloric acid a hydrogen atmosphere ior two hours at room or with alcoholic'potassium carbonate solution. temperature. At the end of this time, the tan:- In each case the yield is ractically theoretical, perature is raised to 70 C. and the hydrosena- (c) A mixture of 1 g. of M- -pregnadienoltion continued for an additional hour and a halt. 3(5) -one-20. 5 g. of aluminum isopropylate and Then the solution is filtered and the solvent re- 100 cc. of dry isopr pyl alcohol is refluxed ior moved under reduced pressure. The residual seven hours. Then the mixtureis slowly dissyrup is allo-pregnanetrioli-3(p),16,20(p) 3- tilled through a short column over a period oi monoacetate-IG-(e-acetoxy)-isocaproate of the live hours. The residue is refluxed with an rollowing formula, excess or 2% alcoholic potassium hydroxide m.

CH: on (J r I n-o w) a While this substance may be further purified by tion for 30 minutes. Then the is diluted crystallization this is not necessary for the next with water, extracted with ether and the ethereal stem solution washed well with water. After removal (d) The above residue is refluxed for fifteen of the ether, the residue is crystallized from ether minutes with a 2% alcoholic potassium hydroxand from dilute acetone to give A'-"-pregnadienide solution. Then the mixture is diluted with did-3(5) 20(5) or melting point 169-171 (I.

.water and the precipitate collected and recrys- On refluxing a'sample 01 this dial with acetic tallized from methanol. The substance thus anhydride and then removing the excess acetic,

anhydrlde by distillation in vacuo, there is obtained A- '-pregnadiendiol-3(p)20(5) diacetate. Aiter crystallization from dilute methanol this diacetate has M. P. 121 C.

The structure of this diol is proved by its hydrogenation to the known allo-pregnanediol-3 (,0) 20(3). For this purpose, a mixture of 50 mg. of A-"-pregnadlendiol-3 (,6) ,20(p) in 20 cc. of ether and 20 cc. of methanol containing a few drops of acetic acid, shaken with 100 mg. of platinum oxide catalyst under pressure of 45 lbs. of hydrogen for one hour. Then the mixture is filtered and the solvents removed. The residue is crystallized from acetone, thereby yielding allo-pregnanediol-3 (p) 20(3) of melting point 192-194 0.

Instead of using M-pregnenediol-Mp),16-one- 20 3-acetate 16-(6-acetoxy)-isocaproate in this example, there may be used other similar esters derived by the oxidation of other esters oi pseudodiosgenin. For example, pseudo-diosgenin dipropionate, pseudo-diosgenin di-n-butyrate, pseudodiosgenin dibenzoate or, in general, any pseudodlosgenin diacylate may be oxidized to yield the corresponding ester and this reduced as described in this or other examples.

Again, instead of using in this example the ester obtained by oxidizing a diacylate oi pseudodiosgenin, there may be used esters obtained by oxidizing the diacylates o1 other pseudo-sapogenins. For instance, this example may e practiced according to parts b and c on allo-pregnanediol- 3(,B),16-one-20 3-acetate 16 (a-acetoxy) -isocaproate oi melting point 102-4 0., as obtained by the oxidation of pseudo-tigogenin diacetate. Thus, hydrolysis of this ester according to part b gives A '-alio-pregnenol-3(p)-one-20 of melting point 204-206 C. Reduction of this compound with aluminum isopropylate and isopropyl alcohol according to the directions 01' part above yields A -allo-pregenediol-3m),2008) of melting point 188-490 C. This substance forms a diacetate oi melting point 102-4 C.

The above examples are intended to illustrate but not to limit the scope of my invention. Other modes of employing my process apparent to those skilled in the art after this disclosure. are intended to fall within the scope of my invention and accordingly I wish to limit the scope of my invention only as indicated in the appended claims.

What I claim as my invention is:

1. Process for preparing hydroxy-pregnane derivatives which comprises subjecting a steroid having in ring D the structure CH: cm =0 I 0 cm m err-01m) 5 fiatives which comprises subiecting a steroid having in ring D the structure CHI CHI 0 D O CH: 0+E-CHr-CHr-H-Cfls-O-acyl to the action of a non-hydrolytic reducing agent, thereby producing a steriod having in ring D the structure and hydrolyzing said steroid with production of a steroid having in ring D the structure 3. Process for preparing hydroxy-pregnane derivatives which comprises catalytically hydrogenating a steroid having in ring D the structure thereby producing a steroid having in ring D the structure 4. Process for preparing hydroxy-pregnane derivatives which comprises subjecting a steroid having in ring D the structure I 2. Process for preparing hydroxy-pregnane de- 5. Process for preparing hydroxy-pregnane derivatives which comprises catalytically hydro- -genating a steroid of the formula- CH: CH: CHI

( II cm O i-cnr-cm-dn-cm o-sm A v where M represents a carbon-to-carbon linkages included between Cl and Ce,'1l having one of the vaiuesandi,andYisamemberoftheciass consisting of hydroxyl and groups hydrolyzable to hydroxyl, thereby producing a steroid of the formula O CHI Ol-OHy-CHs-JIH-CHr-O-dcyl 6. Process for preparing hydroxy-pregnane derivatives which comprises subiecting a steroid of the formula CH: CHI

where as represents a carbon-tc-carbon linkages included between C: and Cs, 1| having one of the values 0 and 1, and Y is a member of the class consisting of hydroxyl and groups hydrolyzable to hydroxyi. to the action of a member of the class consisting of primary alcohols and secondary alcohols. in combination with a member of the class consistins of aluminum alcoholates and compounds of the formula Fug-0R, where Z is an anion and -OR is an alcoholate grouping,

- thereby producing a steroid of the formula CH1 Ce H'OH(I) QMMH-OM-iofl and 'I. A compound representable by the formula CH: CH: 32:

8. A compound representable by the formula on CHI oil-01w) (you cm cm tan-x0e C C H.

til-x0) wherexandx' areeachamemberoftheclass consisting of hydroxyl and groups hydrolysable tohydroxyl.

Rosana-mm. 

